Project Summary More than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States and the estimated annual economic burden of AUD is $249 billion. Approximately 88,000 Americans die from alcohol-related causes each year; untreated AUD is the fourth most preventable cause of death in the US. Four medications have been FDA-approved for treating AUD, but none of these medications have proven to be effective across the heterogeneous groups of drinkers. Treating addiction more effectively is goal with national importance and accelerating drug development for AUD is one of the priorities for NIAAA. This proposal is intended to answer this call for accelerating drug development by exploring the potential of a glucagon-like peptide-1 (GLP-1) agonist, exenatide, as a candidate medication for the treatment of AUD. There is now substantial preclinical evidence that GLP-1 agonists can attenuate behaviors that model both the consumption and seeking of several commonly abused substances including alcohol, cocaine, and nicotine. The GLP-1 agonists Exendin-4 and liraglutide have been shown to reduce alcohol consumption by rodents and attenuate alcohol-induced place preference. Treatment with Exendin-4 blocks increases in alcohol intake following periods of alcohol deprivation, suggesting that this drug may decrease the likelihood of relapse. There is also evidence that Exendin-4 induced reductions in alcohol consumption do not occur in mutant mice who are missing central nervous system GLP-1 receptors. There are no published clinical studies testing the effects of GLP-1 agonists on alcohol consumption. This study is intended to accelerate medication development for AUD by testing a commercially-available and well-tolerated agent at a fraction of the cost of new drug discovery. None of the FDA-approved AUD medications or off-label AUD medications target this GLP-1 pathway, making exenatide a promising compound for AUD drug development. The specific aims of this study are to test the effects of exenatide on 1) alcohol self-administration and craving among heavy drinkers, 2) alcohol absorption, and 3) blood glucose levels during a drinking task. The effects of 5mcg dose of exenatide or sham injection will be evaluated in a human laboratory using an alcohol self-administration method. In this within-subjects crossover design, 36 heavy drinkers will be randomized to exposure order (exenatide or sham injection) prior to completing two alcohol self-administration trials. Subjects will receive a priming drink of alcohol and will have access to 8 drinks over a 2-hour period. We anticipate that subjects will consume less alcohol following the administration of exenatide compared to when they receive a sham injection. Significant exenatide-induced reductions in drinking will be considered to be an indication that this drug may have value as an AUD medication. This study may provide a rationale for phase II RCTs testing exenatide with a treatment-seeking AUD population. These results may also help to spur further clinical investigation of the effects of exenatide and other available GLP-1 agonists on the factors implicated in the regulation of alcohol consumption.